European Journal of Neurology 2005, 12: 331343

EFNS TASK FORCE/CME ARTICLE

Viral encephalitis: a review of diagnostic methods and guidelines

for management
I. Steinera, H. Budkab, A. Chaudhuric, M. Koskiniemid, K. Sainioe, O. Salonenf and
P. G. E. Kennedyc
a
Laboratory of Neurovirology, Department of Neurology, Hadassah University Hospital, Jerusalem, Israel; bInstitute of Neurology, Medical
University of Vienna, Vienna, Austria; cDepartment of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow,
UK; dDepartment of Virology, Haartman Institute, eDepartment of Clinical Neurophysiology, and fHelsinki Medical Imaging Center,
University of Helsinki, Helsinki, Finland

Keywords:
central nervous system,
diagnosis, encephalitis,
guidelines, therapy, virus
Received 6 January 2005
Accepted 6 January 2005
Viral encephalitis is a medical emergency. The spectrum of brain involvement and the
prognosis are dependent mainly on the specic pathogen and the immunological state
of the host. Although specic therapy is limited to only several viral agents, correct
immediate diagnosis and introduction of symptomatic and specic therapy has a
dramatic inuence upon survival and reduces the extent of permanent brain injury in
survivors. We searched MEDLINE (National Library of Medicine) for relevant
literature from 1966 to May 2004. Review articles and book chapters were also
included. Recommendations are based on this literature based on our judgment of the
relevance of the references to the subject. Recommendations were reached by con-
sensus. Where there was lack of evidence but consensus was clear we have stated our
opinion as good practice points. Diagnosis should be based on medical history,
examination followed by analysis of cerebrospinal uid for protein and glucose con-
tents, cellular analysis and identication of the pathogen by polymerase chain reaction
(PCR) amplication (recommendation level A) and serology (recommendation level
B). Neuroimaging, preferably by magnetic resonance imaging, is an essential aspect of
evaluation (recommendation level B). Lumbar puncture can follow neuroimaging
when immediately available, but if this cannot be obtained at the shortest span of time
it should be delayed only in the presence of strict contraindications. Brain biopsy
should be reserved only for unusual and diagnostically dicult cases. All encephalitis
cases must be hospitalized with an access to intensive care units. Supportive therapy is
an important basis of management. Specic, evidence-based, anti-viral therapy, acy-
clovir, is available for herpes encephalitis (recommendation level A). Acyclovir might
also be eective for varicella-zoster virus encephalitis, gancyclovir and foscarnet for
cytomegalovirus encephalitis and pleconaril for enterovirus encephalitis (IV class of
evidence). Corticosteroids as an adjunct treatment for acute viral encephalitis are not
generally considered to be eective and their use is controversial. Surgical decom-
pression is indicated for impending uncal herniation or increased intracranial pressure
refractory to medical management.

pathogen, the immunological state of the host and a

Introduction
Clinical involvement of the central nervous system
(CNS) is an unusual manifestation of human viral
infection. The spectrum of brain involvement and the
outcome of the disease are dependent on the specic
Correspondence: Dr I. Steiner, Department of Neurology, Hadassah
University Hospital, PO Box 12 000, Jerusalem, 91 120, Israel (tel.:
972 2 6776952; fax: 972 2 6437782; e-mail: isteiner@md2.huji.ac.il).
This is a Continuing Medical Education paper and can be found
with corresponding questions on the Internet at: http://www.
blackwellpublishing.com/products/journals/ene/mcqs. Certicates for
correctly answering the questions will be issued by the EFNS.
range of environmental factors. Although specic
therapy is limited to only several viral agents, correct
diagnosis, and supportive and symptomatic treatment
(when no specic therapy is available) are mandatory to
ensure the best prognosis (for reviews see Koskiniemi
et al., 2001; Chaudhuri and Kennedy, 2002; Redington
and Tyler, 2002; Whitley and Gnann, 2002). This
document addresses the optimal clinical approach to
CNS infections caused by viruses.
Classication of evidence levels used in these guide-
lines for therapeutic interventions and diagnostic
measures was according to Brainin et al. (2004) and
detailed in Tables 14.

2005 EFNS 331

332 I. Steiner et al.
Table 1 Evidence classication scheme for a therapeutic intervention
Class I: An adequately powered prospective, randomized, controlled
clinical trial with masked outcome assessment in a representative
population OR an adequately powered systematic review of
prospective randomized controlled clinical trials with masked
outcome assessment in representative populations.
The following are required:
a. Randomization concealment.
b. Primary outcome(s) is/are clearly dened.
c. Exclusion/inclusion criteria are clearly dened.
d. Adequate accounting for dropouts and crossovers with numbers
sufciently low to have minimal potential for bias.
e. Relevant baseline characteristics are presented and substantially
equivalent among treatment groups or there is appropriate
statistical adjustment for differences.
Class II: Prospective matched group cohort study in a representative
population with masked outcome assessment that meets ae above or
a randomized, controlled trial in a representative population that
lacks one criteria ae.
Class III: All other controlled trials (including well-dened natural
history controls or patients serving as own controls) in a
representative population, where outcome assessment is independent
of patient treatment.
Class IV: Evidence from uncontrolled studies, case series, case reports,
or expert opinion.
Table 2 Evidence classication scheme for the rating of recommen-
dations for a therapeutic intervention
Level A rating (established as effective, ineffective, or harmful)
requires at least one convincing class I study or at least two
consistent, convincing class II studies
Level B rating (probably effective, ineffective, or harmful) requires
at least one convincing class II study or overwhelming class III
evidence
Level C (possibly effective, ineffective, or harmful) rating requires
at least two convincing class III studies
Table 3 Evidence classication scheme for a diagnostic measure
Class I: A prospective study in a broad spectrum of persons with the
suspected condition, using a gold standard for case denition, where
the test is applied in a blinded evaluation, and enabling the
assessment of appropriate tests of diagnostic accuracy
Class II: A prospective study of a narrow spectrum of persons with the
suspected condition, or a well-designed retrospective study of a broad
spectrum of persons with an established condition (by gold
standard) compared with a broad spectrum of controls, where test is
applied in a blinded evaluation, and enabling the assessment of
appropriate tests of diagnostic accuracy
Class III: Evidence provided by a retrospective study where either
persons with the established condition or controls are of a narrow
spectrum, and where test is applied in a blinded evaluation
Class IV: Any design where test is not applied in blinded evaluation
OR evidence provided by expert opinion alone or in descriptive
case series (without controls)
Table 4 Evidence classication scheme for the rating of recommen-
dations for a diagnostic measure
Level A rating (established as useful/predictive or not
useful/predictive) requires at least one convincing class I study or
at least two consistent, convincing class II studies
Level B rating (established as probably useful/predictive or not
useful/predictive) requires at least one convincing class II study or
overwhelming class III evidence
Level C rating (established as possibly useful/predictive or not
useful/predictive) requires at least two convincing class III studies
Methods
We searched MEDLINE (National Library of Medi-
cine) for relevant literature from 1966 to May 2004.
The search included reports of research in human
beings only and in English. The search terms selected
were: viral encephalitis, encephalitis, meningoen-
cephalitis and encephalopathy. We then limited the
search using the terms diagnosis, MR, positron
emission tomography (PET), single photon emission
tomography (SPECT), electroencephalography
(EEG), cerebrospinal uid, pathology, treatment
and antiviral therapy. Review articles and book
chapters were also included if they were considered to
provide comprehensive reviews of the topic. The nal
choice of literature and the references included was
based on our judgment of their relevance to this
subject. Recommendations were reached by consensus
of all Task Force participants (Tables 14) and were
also based on our own awareness and clinical experi-
ence. Where there was lack of evidence but consensus
was clear we have stated our opinion as good practice
points (GPP).
Definitions and scope
Encephalitis is the presence of an inammatory process
in the brain parenchyma associated with clinical evi-
dence of brain dysfunction. It can be due to a non-
infective condition such as in acute disseminated
encephalomyelitis (ADEM) or to an infective process,
which is diuse and usually viral. Herpes simplex virus
type 1 (HSV-1), varicella-zoster virus (VZV), Epstein
Barr virus (EBV), mumps, measles and enteroviruses
are responsible for most cases of viral encephalitis in
immuno-competent individuals (Koskiniemi et al.,
2001). Other non-viral infective causes of encephalitis
may include such diseases as tuberculosis, rickettsial
disease and trypanosomiasis, and will be discussed in
the dierential diagnosis section.
Encephalitis should be dierentiated from encephalo-
pathy which is dened as a disruption of brain function

2005 EFNS European Journal of Neurology 12, 331343

that is not because of a direct structural or inamma-
tory process. It is mediated via metabolic processes and
can be caused by intoxications, drugs, systemic organ
dysfunction (e.g. liver, pancreas) or systemic infection
that spares the brain.
The structure of the nervous system determines a
degree of associated inammatory meningeal involve-
ment in encephalitis, and therefore symptoms that re-
ect meningitis are invariable concomitants of
encephalitis. Moreover, in textbooks and review articles
the term viral meningo-encephalitis is often used to
denote a viral infectious process of both the brain/spi-
nal cord and the meninges.
Clinical manifestations and relevant
environmental and personal information
The diagnosis of viral encephalitis is suspected in the
context of a febrile disease accompanied by headache,
altered level of consciousness, and symptoms and signs
of cerebral dysfunction. These may consist of abnor-
malities that can be categorized into four: cognitive
dysfunction (acute memory disturbances), behavioural
changes (disorientation, hallucinations, psychosis, per-
sonality changes, agitation), focal neurological abnor-
malities (such as anomia, dysphasia, hemiparesis,
hemianopia etc.) and seizures. After the diagnosis is
suspected, the approach should consist of obtaining a
meticulous history and a careful general and neuro-
logical examination.
The history
The history is mandatory in the assessment of the
patient with suspected viral encephalitis. It might be
important to obtain the relevant information from an
accompanying person (relative, friend, etc.) if the
patient is in a confused, agitated and disoriented state.
The geographical location as well as the recent travel
history could be of relevance to identify causative
pathogens that are endemic or prevalent in certain
geographical regions (the recent example being severe
acute respiratory syndrome). Likewise, seasonal occur-
rence can be important for other pathogens such as
polio virus. Occupation may well be important (as in a
case of a forestry worker with Lyme disease). Contact
with animals such as farm animals would sometimes
point to the cause, as animals serve as reservoirs for
certain viruses (e.g. West Nile fever and the 1999 out-
break of the disease in New York). A history of insect or
other animal bites can be relevant for arbovirus infec-
tion as well as rabies. Past contact with an individual
aicted by an infective condition is important. The
medical status of the individual is of the utmost

2005 EFNS European Journal of Neurology 12, 331343
EFNS guideline on viral encephalitis 333
relevance. Thus, certain viral and non-viral pathogens
cause encephalitis only or much more frequently in im-
munosuppressed individuals such as patients with AIDS
or those who receive medications that aect the immune
system (e.g. cancer and organ transplant patients).
The mode of disease course up to the appearance of
the neurological signs may provide clues to the aetiol-
ogy. For example, enterovirus infection has a typical
biphasic course. An associated abnormality outside the
nervous system (bleeding tendency in haemorrhagic
fever, the hydrophobia in rabies patients) may also
point to a specic pathogen.
General examination
Viral infection of the nervous system is almost always
part of a generalized systemic infectious disease. Thus,
other organs may be involved prior or in association
with the CNS manifestations. Evidence for such an
involvement should be obtained either from the history
or during the examination. Skin rashes are not in-
frequent concomitants of viral infections, parotitis may
be associated with mumps, gastrointestinal signs with
enteroviral disease and upper respiratory ndings may
accompany inuenza virus infection and HSV-1
encephalitis.
Neurological examination
The ndings relate to those of meningitis and disruption
of brain parenchyma function. Thus, signs of meningeal
irritation and somnolence reect meningitis, while
behavioural, cognitive and focal neurological signs and
seizures reect the disruption of brain function. Addi-
tional signs may include autonomic and hypothalamic
disturbances, diabetes insipidus and the syndrome of
inappropriate antidiuretic hormone secretion. The
symptoms and signs are not a reliable diagnostic
instrument to identify the causative virus. Likewise, the
evolution of the clinical signs and their severity depend
on host and other factors such as immune state and age
and cannot serve as guidelines to identify the pathogen.
In general, the very young and the very old have the
most extensive and serious signs of encephalitis.
Diagnostic investigations
General
Peripheral blood count and cellular morphology, are
helpful in separating viral from non-viral infections.
Lymphocytosis in the peripheral blood is common in
viral encephalitis. Erythrocyte sedimentation rate is
another non-specic test that is usually within normal
334 I. Steiner et al.
range in viral infections. Other, general examinations
such as chest X-ray, blood cultures, belong to the
general work-up of febrile disease.
The auxiliary studies that examine viral infections of
the nervous system include studies that characterize the
extent and nature of CNS involvement (EEG and
neuroimaging), microbiological attempts to identify the
pathogen and histopathology will be discussed here.
EEG is generally regarded as a non-specic investi-
gation, although it is still sometimes a useful tool in
certain situations. Thus, leucoencephalitides shows
more diuse slow activity in the EEG and polioen-
cephalitides shows more rhythmic slow activity (Vas
and Cracco, 1990; Westmoreland, 1999). However, in
practice this hardly helps in the dierential diagnosis.
Likewise, the EEG ndings in post-infectious en-
cephalitides dier from infectious encephalitis only in
the time schedule of the abnormalities. The main benet
of EEG is to demonstrate cerebral involvement during
the early state of the disease. Only in rare instances does
the EEG show specic features that may give clues to
the diagnosis.
Acute viral encephalitis
The EEG is an early and sensitive indicator of cerebral
involvement and usually shows a background abnor-
mality prior to the initial evidence of parenchyma
involvement on neuroimaging. This may in some in-
stances be helpful in the dierential diagnosis of aseptic
meningitis. Often, focal abnormalities may be observed.
During the acute phase, the severity of EEG abnor-
malities do not usually correlate with the extent of the
disease. However, a fast improving EEG indicates a
good prognosis, while lack of improvement of the EEG
recording carries a non-favorable prognosis (Vas and
Cracco, 1990, class IV). Although there may be seizures
in the acute phase, interictal epileptiform EEG activity
is a rarity. The EEG abnormalities usually subside more
slowly than the clinical symptoms (Westmoreland,
1999).
Herpes simplex encephalitis
In 80% of the patients there is a typical nding in the
EEG. In addition to the background slowing there is a
temporal focus showing periodic lateralized epilepti-
form discharges. This nding is temporary; it can be
found during days 214 from the beginning of the dis-
ease, most often during days 510 (Lai and Gragasin,
1988). Detection of this EEG nding often requires
serial recordings. The repetition interval of these pseu-
doperiodic complexes is from 1 to 4 s; in newborns it
can be faster with a frequency of 2 Hz. Also the local-
ization in newborns may be other than temporal (Sainio
et al., 1983).
Brain-stem encephalitis
In brain-stem encephalitis the EEG mainly reects the
lowered consciousness and the abnormalities can be
mild compared with the clinical state of the patient.
Intermittent rhythmic delta activity (IRDA) has also
been described in these patients.
Cerebellitis
In cerebellitis the EEG is mostly normal (Schmahmann
and Sherman, 1998).
HIV
The EEG pattern in human immunodeciency virus
(HIV) infection of the brain is very variable, with
background, paroxysmal and focal abnormalities
(Westmoreland, 1999). Likewise the ndings in ADEM
are unspecic encephalitic abnormalities (Tenembaum
et al., 2002).
Subacute sclerosing panencephalitis
The EEG in subacute sclerosing panencephalitis (SSPE)
shows a typical generalized periodic EEG pattern
repeating with intervals between 4 and 15 s and syn-
chronized with myoclonus of the patient (West-
moreland, 1999)
Neuroimaging of encephalitis
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is more sensitive
and specic than CT for the evaluation of viral
encephalitis (Dun et al., 1986; Schroth et al., 1987;
Dale et al., 2000; Marchbank et al., 2000, class IIIC).
The advantages of MRI include the use of non-ion-
izing radiation, multiplanar imaging capability, im-
proved contrast of soft tissue, and high anatomical
resolution. On the basis of previous data it should be
the imaging technique of choice in determination of
encephalitis. It allows earlier detection and treatment
of inammatory processes. MRI also provides valu-
able information for patient follow-up. However, in
practical terms many patients with suspicion of
encephalitis often undergo CT scanning before neuro-
logical consultation.
A typical MRI protocol consists of routine T1 and
T2 spin-echo sequences and a uid-attenuation
inversion recovery (FLAIR) sequence, which is con-
sidered extremely sensitive in detecting subtle changes
in the early stages of an acute condition. Gradient-
echo imaging, with its superior magnetic susceptibil-
ity, is also useful in detecting small areas of
haemorrhage.
New MR imaging techniques are being applied to the
study of various brain diseases. These technologies

2005 EFNS European Journal of Neurology 12, 331343

include procedures that can increase sensitivity to small,
yet clinically relevant lesions, these techniques may be
useful for imaging protocols of patients with suspicion
of encephalitis:
(i) Diffusion-weighted MRI (DWI) enables separation of
cytotoxic from vasogenic oedema and distinguishes re-
cent from old insult, which can often be dicult on
routine T2 and FLAIR imaging.
(ii) Low magnetization transfer ratio (MTR) reects
myelin damage, cell destruction or changes in water
content.
(iii) Magnetic resonance spectroscopy (MRS) identies
and quantities concentration of various brain metabo-
lites. Spectroscopy is capable of dierentiating normal
from pathological brain and provides tissue specicity
greater than that of imaging instances.
(iv) Functional MRI (FMRI) uses very rapid scanning
techniques that in theory can demonstrate alterations in
blood oxygenation.
CT
CT is recommended only as a screening examination
with subtle clinical suspicion of encephalitis or when
MRI is unavailable (Dun et al., 1986; Schroth et al.,
1987; Marchbank et al., 2000, class IV).
SPECT
SPECT is more readily available than PET and has
been utilized in the study and diagnosis of encephalitis
(Launes et al., 1988). It can provide information about
brain chemistry, cerebral neurotransmitters and brain
function. It can also demonstrate hypoperfused tissue
that seems normal on structural imaging.
PET
Although the gold standard in acquiring functional
imaging data, remains a complex, costly and not readily
available technique.
In summary, structural information is provided by
CT scan and MRI while functional and metabolic data
are provided by MRS, FMRI, SPECT and PET.
Imaging of specic disorders
Herpes simplex encephalitis. CT obtained early is often
normal or subtly abnormal. Low attenuation, mild mass
eect in temporal lobes and insula, haemorrhage and
enhancement are late features. Follow-up scans 1
2 weeks after disease onset demonstrate progressively
more widespread abnormalities with the involvement of
contra lateral temporal lobe, insula and cingulate gyri.
Contrast enhancement and changes of subacute hae-
morrhage may become readily apparent. MRI is much
more sensitive in detecting early changes (Schroth et al.,
1987; Marchbank et al., 2000; Chaudhuri and Kennedy,

2005 EFNS European Journal of Neurology 12, 331343
EFNS guideline on viral encephalitis 335
2002, class IIIC). Involvement of cingulate gyrus and
contra lateral temporal lobe is highly suggestive of
herpes encephalitis. Typical early ndings include gyral
oedema on T1-weighted (T1WI) imaging and high signal
intensity in the temporal lobe or cingulate gyrus on
T2WI, FLAIR and DWI and later haemorrhage.
Hypointense on T1, hyperintense on T2WI, FLAIR,
high signal on DWI are additional ndings (Ito et al.,
1999; Tsuchiya et al., 1999). In acute lesions, MRS re-
veals metabolic changes in relation to neuronal death
such as a decrease of N-acetyl aspartate (NAA) signal.
Resultant gliosis is reected as an increase in inositol
and creatine resonances. The reinstitution of a normal
spectrum over time could then potentially be used as a
marker of treatment ecacy (Menon et al., 1990; Salvan
et al., 1999).
Neonatal HSV-2 infection often causes more wide-
spread signal abnormalities than HSV-1 encephalitis,
with periventricular white matter involvement and
sparing of the medial temporal and inferior frontal
lobes (Hinson and Tyor, 2001).
HIV-1. CT demonstrates normal/mild atrophy with
white matter hypodensity. MRI usually shows atrophy
and non-specic white matter changes. MRS detects
early decreases in levels of NAA and increases in cho-
line-containing phospholipids (Cho) levels, even before
abnormalities are detected by MRI and prior to clinical
symptoms. Later, with cognitive dysfunction, further
reductions in NAA and increases in Cho levels may be
seen (Rudkin and Arnold, 1999). In the later stages of
AIDS, the most common diseases aecting the brain
parenchyma are secondary to opportunistic infection or
malignancy and are predominantly focal. Neuroimag-
ing is an important diagnostic tool for opportunistic
infections. Toxoplasmosis (ring enhancing mass(es) in
basal ganglia), cryptococcosis (gelatinous pseudo-
cysts), meningoencephalitis, vasculitis, infarction,
cytomegalovirus (CMV)-encephalitis (diuse white
matter hyperintensities), ventriculitis (ependymal
enhancement), progressive multifocal leucoencephal-
opathy (PML, white matter hyperintensities which
usually do not enhance), lymphoma (solitary or multi-
focal solid or ring-enhancing lesions either in deep grey
and white matter or less frequent in subcortical areas)
(Thurnher et al., 2001; Yin et al., 2001). MRS may
be able to distinguish between these dierent space-
occupying lesions based on their chemical proles.
1H-magnetic resonance spectroscopy can serve to
monitor the ecacy of antiretroviral therapy and may
even be used to predict the responsiveness to drug
therapy (Wilkinson et al., 1997).
VZV. CNS complications of VZV infection (usually
caused by reactivation) include myelitis, encephalitis,
large- and small-vessel arteritis, ventriculitis, and
336 I. Steiner et al.
meningitis (Gilden et al., 2000). Large vessel arteritis
presents with ischemic/haemorrhagic infarctions and
MRI supported by angiography usually reveals these
complications (Gilden et al., 2000; Redington and
Tyler, 2002).
Miscellaneous viral infections. In polio and coxsackie
virus infections, T2-weighted MRI may show hyperin-
tensities in the midbrain and anterior horn of spinal
cord (Shen et al., 2000). In EBV infection hyperinten-
sities in the basal ganglia and thalami may be observed
on T2-weighted MRI (Shian and Chi, 1996). West Nile
virus (WNV) can be associated with enhancement of
leptomeninges, the periventricular areas, or both, on
MRI (Sejvar et al., 2003). T2-weighted MRI of Japan-
ese encephalitis can show hyperintensities in bilateral
thalami, brainstem and cerebellum.
ADEM. Initial CT may show low density, occulent,
asymmetric lesions with mild mass eect and contrast
enhancement multifocal punctate or ring-enhancing
lesions. However, CT is normal in 40% of cases. MRI is
more sensitive and an essential diagnostic tool. T2WI
and FLAIR scans present multifocal, usually bilateral,
but asymmetric and large hyperintense lesions, invol-
ving peripheral white and grey matter. They do not
usually involve the callososeptal interface. Contrast-
enhanced T1-weighted images may show ring-enhan-
cing lesions. Cranial nerves may enhance. DWI is
variable. On MRS, NAA is transiently low and choline
is normal (Schroth et al., 1987; Dale et al., 2000; Bizzi
et al., 2001).
PML. MRI is also the most sensitive imaging tool for
PML (Berger and Major, 1999). T2-weighted sequences
initially show multiple, bilateral, non-enhancing, oval
or round subcortical white matter hyperintensities in
the parietooccipital area. Conuent white matter dis-
ease with cavitary change is a late manifestation of
PML. Less common imaging manifestations of PML
are unilateral white matter and thalamic or basal gan-
glia lesions.
Rasmussens encephalitis. Rasmussens encephalitis
(RE) typically involves only one cerebral hemisphere,
which becomes atrophic. The earliest CT and MRI
abnormalities include high signal on T2-weighted MR
images in cortex and white matter, cortical atrophy that
usually involves the fronto-insular region, with mild or
severe enlargement of the lateral ventricle and moderate
atrophy of the head of the caudate nucleus. Fluorode-
oxyglucose PET has been reported to present hypo-
metabolism; Tc-99m hexamethylpropyleamine oxime
SPECT decreased perfusion and proton MRS reduction
of NAA in the aected hemisphere. However, PET and
SPECT ndings are non-specic. MRI may become a
valuable early diagnostic tool by demonstrating focal
disease progression (Chiapparini et al., 2003).
Paraneoplastic limbic encephalitis. In paraneoplastic
limbic encephalitis MRI FLAIR and DWI depict
bilateral involvement of the medial temporal lobes and
multifocal involvement of the brain. T2-weighted turbo
spin-echo images fail to show changes (Thuerl et al.,
2003).
Virological tests in encephalitis
General
The gold standard of diagnosis in encephalitis is virus
isolation in cell culture, now to be replaced by the
detection of specic nucleic acid from CSF or brain
(Rowley et al., 1990; Echevarria et al., 1994; Lakeman
and Whitley, 1995; Tebas et al., 1998, class Ia). Intra-
thecal antibody production to a specic virus is simi-
larly a strong evidence for aetiology (Levine et al.,
1978; Koskiniemi et al., 2002, class Ib). Virus detection
from throat, stool, urine or blood as well as systemic
serological responses like seroconversion or a specic
IgM provides less strong evidence (Burke et al., 1985;
Koskiniemi et al., 2001, class III). The CSF is a con-
venient specimen and is recommended for neurological
viral diagnosis in general (Cinque and Linde, 2003).
Brain biopsy is invasive and not used in routine clinical
practice. At autopsy brain material will be obtained for
virus isolation, nucleic acid and antigen detection as
well as for immunohistochemistry and in situ hybridi-
zation.
Viral culture
Viral cultures from CSF and brain tissue as well as from
throat and stool specimens are performed in four dif-
ferent cell lines: African green monkey cells, Vero cells,
human amniotic epithelial cells and human embryonic
skin broblasts. Cells are evaluated daily for cytopathic
eect and the ndings are conrmed by a neutralizing
or an immunouorescence antibody test. Viral cultures
from CSF are positive in young children with entero-
viral infection but only seldom, in <5%, in other cases
(Muir and van Loon, 1997; Storch, 2000, class III). As
brain biopsy is reserved only for unusual and diagnos-
tically dicult cases, viral cultures are only rarely
available from brain tissues
Nucleic acid detection
For nucleic acid detection, polymerase chain reaction
(PCR) technology provides the most convenient test.
Assays for HSV-1, HSV-2, VZV, human herpesvirus 6
and 7, CMV, EBV, enteroviruses and respiratory vir-
uses as well as for HIV can be performed from CSF
samples or brain tissue. The primers are selected from a
conserved region of the viral genome and the PCR
product is identied by hybridization with specic

2005 EFNS European Journal of Neurology 12, 331343

probes or by gel electrophoresis. Respiratory viruses
nucleic acid as well as Chlamydia pneumoniae and
Mycoplasma pneumoniae can also be detected from
throat samples and enterovirus nucleic acid from stool
samples. However, these cannot conrm the aetiology
of encephalitis. PCR for C. pneumoniae can also be
performed from a CSF sample. Detection of specic
nucleic acid from the CSF depends on the timing of
CSF sample. The highest yield is obtained during the
transient appearance of the virus in the CSF compart-
ment during the rst week after symptom onset, much
less in the second week and only occasionally after that
(Lakeman and Whitley, 1995; Koskiniemi et al., 2002,
class I). In herpes simplex encephalitis (HSE) the sen-
sitivity is 96% and the specicity 99% when CSF is
studied between 48 h and 10 days from the onset of
symptoms (Lakeman and Whitley, 1995; Tebas et al.,
1998).
Instead of the single PCR tests, the multiplex PCR
are gaining ground in diagnostics (Tenorio et al., 1993;
Pozo and Tenorio, 1999). The sensitivity has been im-
proved and it approaches that of the single PCR and
the specicities are equal. Real-time PCR makes it
possible to get the result in a shorter time while
observing the yield cycle by cycle (Kessler et al., 2000).
The usage of microarrays for detection of viral nucleic
acid is still expensive, but has the potential to become a
regular diagnostic technique. Several microbes can be
studied at the same time and identication of the
genotype will be easier than using the current conven-
tional methods.
Serological tests
Antibodies to HSV-1, HSV-2, VZV, CMV, HHV-6,
HHV-7, CMV, EBV, respiratory syncytial virus (RSV),
HIV, adeno, inuenza A and B, rota, coxsackie B5,
non-typed entero and parainuenza 1 viruses as well as
Mycoplasma pneumoniae are measured from serum and
CSF by using enzyme immunoassay (EIA) tests and
antibodies for Chlamydia pneumoniae by microimmu-
nouorescence test (MIF) (MacCallum et al., 1974;
Levine et al., 1978; Julkunen et al., 1984; Socan et al.,
1994; Koskiniemi et al., 1996; Gilden et al., 1998;
Koskiniemi et al., 2001, class II). These tests are sensi-
tive enough to detect even low amounts of antibodies
from the CSF. The antibody levels in serum and CSF
are compared with each other in the same dilution of
1:200. If the ratio of antibody levels is 20, it indicates
intrathecal antibody production within the brain pro-
vided that no other antibodies are present in the CSF,
i.e. the bloodbrain barrier (BBB) is not damaged. The
presence of several antibodies in the CSF suggests BBB
breakdown, while the presence of specic IgM in the
CSF indicates CNS disease (Burke et al., 1985). The

2005 EFNS European Journal of Neurology 12, 331343
EFNS guideline on viral encephalitis 337
tests for measles, mumps and rubella are only occa-
sionally needed in countries with eective vaccination
programmes. Tests for arboviruses and zoonoses will be
useful in endemic areas (Burke et al., 1985; Wahlberg
et al., 1989).
Antigen detection
Antigens of HSV, VZV and RSV, inuenza A and B,
parainuenza 1 and 3, and adenoviruses can be studied
from throat specimens with a conventional immuno-
uorescence (IF) test or with an EIA test and may
provide a possible aetiology for encephalitis. In spite of
promising initial results these tests are not helpful in
diagnosis using CSF samples.
In conclusion, in a patient with suspected encephalitis
obtaining serum and CSF for virological tests is the
core of diagnostic procedure. Tests should include:
PCR (single, multiplex or microarray) test for nucleic
acid detection (from CSF) and serological tests for
antibodies (from CSF and serum samples). In undiag-
nosed severe cases, PCR should be repeated after 3
7 days, and serological tests repeated after 24 weeks to
show possible seroconversion or diagnostic increase in
antibody levels. In children, viral culture from throat
and stool samples as well as antigen detection for herpes
and respiratory viruses are recommended during the
rst week. Viral culture from CSF is useful in children
with suspected enteroviral or VZV disease if PCR tests
are not available.
Histopathology
Encephalitis features a variety of histopathological
changes in the brain, mainly depending upon the type
of the infectious agent, the immunological response by
the host, and the stage of the infection. The aetiological
spectrum is strongly inuenced by geography. It should
also be noted that primary encephalitic processes may
secondarily involve the meninges as well, with inam-
matory inltration resulting in usually mild CSF pleo-
cytosis (lymphocytes with variable degree of activation,
eventually plasmocytes). In encephalitis with a prom-
inent necrotizing component, mixed CSF cellularity
may also include granulocytes; this is frequently seen in
HSV encephalitis, and CMV (peri)ventriculitis/myel-
oradiculitis of HIV patients.
The histopathological basis of encephalitis is the triad
of damage to the parenchyma (usually nerve cell dam-
age or loss, eventually demyelination), reactive gliosis
and inammatory cellular inltration (by haematogen-
ous elements in the immunocompetent host) (Budka,
1997).
This classical substrate is exemplied by (multi)nod-
ular encephalitis, as in the majority of viral encephali-
tides consisting of nerve cell damage, followed by nerve
338 I. Steiner et al.
cell death and neuronophagia, focal/nodular prolifer-
ation of astro- and microglia, and focal/nodular inl-
tration by lymphocytes, eventually macrophages. Thus,
the classical encephalitic nodules are composed of
the mixture of microglia, astrocytes and lymphocytes
usually around aected neuron(s) (Budka, 1997).
Distribution and spread of these inammatory
changes are important for aetiological considerations:
six types of encephalitis may be distinguished, either
focal or diuse aecting either the grey matter, the
white matter, or both (Love and Wiley, 2002). The
encephalitic patterns include continuous polioen-
cephalitis (e.g. in luetic general paresis) and patchy-
nodular polioencephalitis (e.g. in poliomyelitis, rabies,
acute encephalitis by avi-, toga- and enteroviruses,
HSV brainstem encephalitis), leucoencephalitis (e.g. in
PML or HIV leucoencephalopathy), and panen-
cephalitis (e.g. in bacterial septicaemia with micro-
abscesses, in Whipples disease, SSPE, HIV
encephalitis, and herpesviruses such as HSV, CMV
and VZV infection). Abscesses and granulomas may
be randomly distributed in the brain. In addition to
the inammatory quality and characteristic distribu-
tion of tissue lesions, cytological features such as
inclusion bodies (intranuclear in HSV, VZV enceph-
alitis, PML and SSPE, cytoplasmic Negri bodies in
rabies) or cytomegalic cell change in CMV disease give
important diagnostic clues, especially when the
involved cell type is considered: every viral infection of
the nervous system usually features a ngerprint
signature of selective vulnerability in the nervous
system (Budka, 1997). However, immunosuppression
and the eects of potent therapies have become
notorious for being able to modify, blur or even wipe
out the classical features of specic viral lesions.
The role of special techniques: immunocytochemistry,
in situ hybridization, PCR
Arguably, it is in the eld of infections where the
techniques of immunocytochemistry (ICC), in situ
hybridization (ISH) and PCR have the most profound
impact on neuropathological diagnosis. When per-
formed appropriately with adequate controls and ade-
quate tissue selection, they provide an aetiological
diagnosis with high sensitivity and specicity (Budka,
1997; Johnson, 1998). Nevertheless, there are caveats
for situations in which they may not be diagnostic:
(i)Production of the infectious agent may have burnt
out, or its products may have become masked, resulting
in negative ICC or ISH.
(ii)Tissue preservation might be unsuitable for these
techniques, e.g. ICC or ISH may be falsely negative on
overxed tissue, or nucleic acid amplication from
paran-embedded tissue by PCR may be blocked by
yet unidentied factors.
(iii)As PCR and ISH are very sensitive techniques,
positive results may just reect the presence of genomic
information resulting from dormant or latent, and not
necessarily productive and pathogenic infection.
Therefore, prerequisites for the use of ICC, ISH or PCR
for neuropathological diagnosis of infections include
simultaneous use of known positive and negative con-
trol tissues which were identically processed as the
material to be examined; availability of reagents (anti-
bodies, probes, primers) with dened specicities; ade-
quate testing of reagents on control tissues for highest
sensitivity and sensitivity (optimal signal to noise ratio)
in the respective laboratory and experience with im-
munocytochemical antigen retrieval techniques such as
enzyme digestion, microwave treatment or autoclaving
(Budka, 1997).
Viruses may exert damage to the nervous system not
only by productive virus infection of the nervous sys-
tem, but by indirect means as well. The best example is
the immune-mediated ADEM or post-infectious/perive-
nous encephalitis as a sequel of exanthematous viral
disease of childhood (e.g. measles, varicella, rubella,
mumps, inuenza). This is very important for dier-
ential diagnosis from productive viral encephalomyeli-
tis: multiple small demyelinated foci are arranged
around small veins of the white matter, featuring
cellular inltration composed by lymphocytes,
macrophages and microglia (Budka, 1997).
Other infective causes of
meningoencephalitis and differential
diagnosis
Clinical distinction between viral encephalitis and non-
viral infective meningoencephalitis is dicult, often
impossible. Epidemiological and demographic features,
such as prevalent or emergent infections in the com-
munity, occupation, a history of travel and animal
contacts may provide helpful clues. In acute bacterial
meningitis, meningeal symptoms of intense headache,
photophobia and vomiting appear early and are usually
more severe than the encephalopathic features. Presence
of multiple cranial neuropathies is also suggestive of a
primary meningeal process. History of continued fever
and a subacute onset of symptoms with progressive
obtundation and/or features of raised intracranial
pressure are more typical of suppurative intracranial
infections such as brain abscess. Tuberculous meningitis
(TBM) also presents similarly, and in children, symp-
toms of TBM are often subacute in onset. In a non-
epidemic setting, the most common cause of focal
encephalopathic ndings is HSE; however, among cases

2005 EFNS European Journal of Neurology 12, 331343

with biopsy-proven herpes encephalitis, there were no
distinguishing clinical characteristics between patients
positive for HSV and those who were negative (Whitley
and Gnann, 2002).
ADEM
ADEM, an autoimmune disease, with evidence of cell-
mediated immunity to the myelin basic protein as its
pathogenic basis (Behan et al., 1968), is characterized
by focal neurological signs and a rapidly progressive
course in a usually apyrexial patient, usually with a
history of febrile illness or immunization preceding the
neurological syndrome by days or weeks (post-infec-
tious or post-vaccinal encephalomyelitis). It may be
distinguished from infective encephalitis by the younger
age of the patient, prodromal history of vaccination or
infection, absence of fever at the onset of symptoms and
the presence of multifocal neurological signs aecting
optic nerves, brain, spinal cord and peripheral nerve
roots. ADEM classically presents as a monophasic ill-
ness developing after certain viral infections or immu-
nizations (post-infective and post-vaccinal ADEM). In
the prodromal phase, patients experience migrainous-
type headache with meningism. The disturbances of
consciousness range from stupor and confusion to
coma. There is usually preservation of the abdominal
reexes and patients have a mild fever often with per-
ipheral blood pleocytosis. CSF shows lymphocytic
pleocytosis, with mildly raised protein and may appear
similar to the CSF in viral encephalitis. The clinical
course of patients with Hashimotos encephalopathy
would t a less aggressive form of recurrent ADEM
(Chaudhuri and Behan, 2003).
CNS vasculitis
CNS vasculitis can be part of a systemic disease or be
conned to the nervous system. Systemic symptoms,
aseptic meningitis and focal neurological decit may
occasionally simulate viral encephalitis. This is seen in
both systemic vasculitis and primary CNS angiitis. In
systemic vasculitis aecting the CNS it is usually
possible to make a diagnosis based on a combination of
systemic and CSF serological and immunological tests
and angiographic appearances of CNS vasculitis. In
isolated angiitis diagnosis may be more challenging and
even require brain and meningeal biopsy to secure the
diagnosis where diagnostic uncertainties persist.
Pseudomigraine with pleocytosis
Acute confusion, psychosis and focal neurological
decit (hemiplegia, hemianaesthesia and aphasia) in

2005 EFNS European Journal of Neurology 12, 331343
EFNS guideline on viral encephalitis 339
association with migraine headache occur in familial
hemiplegic migraine (Feely et al., 1982). Sterile CSF
pleocytosis (pseudomigraine) has been reported in
migraine patients who may present similarly (Schraeder
and Burns, 1980). It has been proposed that the CSF
pleocytosis in some of these cases is due to recurrent
predisposition to viral meningitis (Casteels-van Daele
et al., 1981). Pseudomigraine with pleocytosis and
migraine coma are likely to represent reversible forms
of ADEM (Chaudhuri and Behan, 2003).
Therapy
Anti-viral therapy
In two randomized controlled trials, acyclovir (10 mg/
kg every 8 h given intravenously for 10 days) was found
to be more eective than vidarabine (15 mg/kg/day) in
improving survival rates of adult patients with biopsy-
proven HSE (Skoldenberg et al., 1984; Whitley et al.,
1986). Acyclovir is a safe treatment and given the higher
risk associated with diagnostic brain biopsy, it has be-
come an established practice that treatment for viral
encephalitis is commenced on suspicion before a specic
aetiological diagnosis is possible (Chaudhuri and Ken-
nedy, 2002). When given early in the clinical course of
HSE before the patient becomes comatose, acyclovir
reduces both mortality and morbidity in treated pa-
tients. Acyclovir is also the treatment of choice for
neonatal HSE; however, there is no denitive evidence
from trials that it is more eective than vidarabine.
Acyclovir has a relatively short half-life in plasma and is
usually given intravenously 10 mg/kg every 8 h in
adults (total daily dose 30 mg/kg). The daily dose of
acyclovir for neonatal HSE is 60 mg/kg (double the
adult dose). As more than 80% of acyclovir in circu-
lation is excreted unchanged in urine, renal impairment
can rapidly precipitate acyclovir toxicity and thera-
peutic doses should be adjusted according to the renal
clearance. Rare relapses of HSE have been reported
after weeks to 3 months later when the duration of
acyclovir treatment was 10 days or less (Davis, 2000).
With conventional therapy, relapses of HSE may be
higher than expected (5%) but do not occur if higher
doses were administered for 21 days (Ito et al., 2000).
Although there have been no randomized trials, an
accepted policy in clinical practice is to give acyclovir
treatment for CSF PCR-positive HSE for 14 days in
immunocompetent adult patients and 21 days for im-
munosuppressed patients. Use of vidarabine for HSE is
limited to the unlikely and rare patients who cannot
receive acyclovir because of side-eects.
Besides HSV, acyclovir is also eective against VZV
and the doses and duration of therapy for VZV
340 I. Steiner et al.
encephalitis are similar to HSE (GPP). In CMV
encephalitis, combination therapy with ganciclovir
(5 mg/kg intravenously twice daily) with foscarnet
(60 mg/kg every 8 h or 90 mg/kg every 12 h) is currently
advised (GPP). Acyclovir is ineective in CMV enceph-
alitis. Antiretroviral therapy must be added or continued
in HIV infected patients (Portegies et al., 2004).
No antiviral therapy is particularly eective in epi-
zootic or enzootic viral encephalitis; however, because
of the high mortality rate associated with B virus (cer-
copithecine herpesvirus) encephalitis in humans, it is
currently proposed (Whitley and Gnann, 2002) that
patients should be treated with intravenous acyclovir or
ganciclovir.
Newer antivirals like valciclovir appear promising in
HSV and VZV encephalitis but remain to be evaluated
by formal trials (Biran and Steiner, 2002). Pleconaril is
a new broad spectrum antiviral with potential for use
in enteroviral encephalitis and is undergoing clinical
evaluation (Pevear et al., 1999).
Corticosteroids
Large doses of corticosteroids (dexamethasone) as an
adjunct treatment for acute viral encephalitis are not
generally considered to be eective and their use is
controversial. Probably the best evidence for steroid
therapy is in VZV encephalitis. Primary VZV infection
may cause severe encephalitis in immunocompetent
children due to cerebral vasculitis (Hausler et al., 2002).
Vasculitis following primary and secondary VZV
infection is recognized to lead to a chronic course in
immunocompetent children and adults (granulomatous
angiitis). HSE is occasionally complicated by severe,
vasogenic cerebral oedema with CT or MRI evidence of
midline shift where high dose steroids may have a role.
Steroid pulse therapy with methylprednisolone has been
observed to be benecial in a small number of patients
with acute viral encephalitis who had progressive dis-
turbances of consciousness, an important prognostic
factor for outcome (Nakano et al., 2003).
Based on available data, combined acyclovir/steroid
treatment may be advised in immunocompetent indi-
viduals with severe VZV encephalitis and probably in
other cases of acute viral encephalitis where progressive
cerebral oedema documented by CT/MRI complicates
the course of illness in the early phase (GPP). High dose
dexamethasone or pulse methylprednisolone are both
suitable agents. The duration of steroid treatment
should be short (between 3 and 5 days) in order to
minimize adverse eects (e.g. gastrointestinal haemor-
rhage, secondary fever and infections).
Although no randomized controlled trials have
been performed, treatment with high dose steroids
(intravenous pulses of methylprednisolone) and/or
plasma exchange is usually the recommended treatment
in ADEM (Cohen et al., 2001, class IV and GPP).
Surgical intervention
Surgical decompression for acute viral encephalitis is
indicated for impending uncal herniation or increased
intracranial pressure refractory to medical management
(steroids and mannitol, GPP). Such intervention has
been shown to improve outcome in HSE in individual
cases (Yan, 2002).
General measures
All cases of acute encephalitis must be hospitalized. Like
other critically ill patients, cases with acute viral
encephalitis should have access to intensive care unit
equipped with mechanical ventilators. Irrespective of the
aetiology, supportive therapy for acute viral encephalitis
is an important cornerstone of management (Chaudhuri
and Kennedy, 2002). Seizures are controlled with intra-
venous phenytoin. Careful attention must be paid to the
maintenance of respiration, cardiac rhythm, uid bal-
ance, prevention of deep vein thrombosis, aspiration
pneumonia, medical management of raised intracranial
pressure and secondary bacterial infections. Secondary
neurological complications in the course of viral
encephalitis are common and include cerebral infarction,
cerebral venous thrombosis, syndrome of inappropriate
ADH secretion, aspiration pneumonia, upper gastroin-
testinal bleeding, urinary tract infections and dissemin-
ated intravascular coagulopathy.
Isolation for patients with community acquired acute
infective encephalitis is not required. Consideration of
isolation should be given for severely immunosup-
pressed patients, rabies encephalitis, patients with an
exanthematous encephalitis and those with a conta-
gious viral haemorrhagic fever.
Rehabilitation
Survivors of viral encephalitis and myelitis are a
heterogenous group. Nature of the infective pathogen,
variability in anatomic lesions and time to treatment
contribute to outcome. Longitudinally designed case
studies, reporting cognitive and psychosocial outcome
following mainly herpes simplex virus encephalitis were
conducted prior to current era of early diagnosis and
eective therapy. While there are anecdotal case reports
(Wilson et al., 2001; Miotto, 2002, and others) there
are too few studies on the outcome of rehabilitation
following encephalitis (Moorthi et al., 1999) to enable
to draw any conclusions.

2005 EFNS European Journal of Neurology 12, 331343
 EFNS guideline on viral encephalitis 341

Preventive measures Recommendations for therapeutic

interventions
Currently vaccines are available against a limited
number of viruses with a potential to cause encephalitis. The following are the specic and symptomatic thera-
Universal immunization is recommended against peutic measures available for viral encephalitis
mumps, measles, rubella and poliovirus. European
travellers to specic geographical destinations (e.g. Class of level of
Southeast Asia) should receive advice regarding vac- Interventions evidence recommendation
cination against rabies and Japanese encephalitis. Pre-
Acyclovir for HSE II A
ventive measures against exotic forms of emerging
Acyclovir for suspected IV ())
paramyxovirus encephalitis (Nipah and Hendra vir- viral encephalitis
uses) are entirely environmental (sanitation, vector Acyclovir for VZV IV ())
control and avoidance). encephalitis
Gancylovir and/foscarnet IV ())
for CMV encephalitis
Recommendations for diagnostic tests Acyclovir or ganciclovir IV ())
for B virus encephalitis
Viral encephalitis is still an evolving discipline in Pleconaril for enterovirus Not available ())
medicine. The emergence of new, and re-emergence of encephalitis
old pathogens and the constant search for specic Corticosteroids IV
for viral encephalitis
therapeutic measures, unavailable in most viral
Surgical decompression IV
encephalitis cases, suggests that the following years
will bring new developments in diagnosis and ther-
apy. At present, adherence to a strict protocol These guidelines will be updated when necessary and
of diagnostic investigations is recommended and in any case in not more than 3 years.
includes:
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